Xue Mengzhou, Hollenberg Morley D, Demchuk Andrew, Yong V Wee
Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, 3330 Hospital Drive, Calgary, Alberta T2N 4N1, Canada.
Stroke. 2009 Jun;40(6):2199-204. doi: 10.1161/STROKEAHA.108.540393. Epub 2009 Apr 9.
To reduce bleeding and damage to central nervous system tissue in intracerebral hemorrhage, the coagulant effect of thrombin is essential. However, thrombin itself can kill neurons in intracerebral hemorrhage as can the matrix metalloproteinases (MMPs), which are also elevated in this condition, in part due to thrombin-mediated activation of MMPs. It is thus important to understand and block the neurotoxic effects of thrombin without inhibiting its therapeutic outcomes. In this study, we have investigated the relative roles of proteinase activated receptor-1, a thrombin receptor, and MMPs in brain injury induced by thrombin or blood.
Mice were subjected to stereotactic intracerebral injections of saline, thrombin, and autologous blood, with or without hirudin, a thrombin inhibitor, or GM6001, an MMP inhibitor. Twenty-four hours later, tissue sections were obtained to evaluate the area of brain damage and extent of dying neurons. Data from wild-type mice were compared with results obtained with proteinase activated receptor-1 null mice.
In blood-induced damage to the brain parenchyma, both hirudin and GM6001 significantly reduced injury to a comparable extent (>40%) implicating both thrombin and MMPs in neurotoxicity. In proteinase activated receptor-1 null mice, blood-induced brain damage was reduced by 22.6% relative to wild-type animals; by comparison, the blood-induced brain damage was reduced by 48.3% using GM6001.
The neurotoxicity of blood in intracerebral hemorrhage involves both proteinase activated receptor-1 and MMP activation, with the latter appearing more prominent in causing death.
为减少脑出血时中枢神经系统组织的出血和损伤，凝血酶的凝血作用至关重要。然而，凝血酶本身可杀死脑出血中的神经元，基质金属蛋白酶（MMPs）也可如此，在这种情况下MMPs水平也会升高，部分原因是凝血酶介导的MMPs激活。因此，了解并阻断凝血酶的神经毒性作用而不抑制其治疗效果很重要。在本研究中，我们调查了蛋白酶激活受体-1（一种凝血酶受体）和MMPs在凝血酶或血液诱导的脑损伤中的相对作用。
对小鼠进行立体定向脑内注射生理盐水、凝血酶和自体血，同时给予或不给予水蛭素（一种凝血酶抑制剂）或GM6001（一种MMP抑制剂）。24小时后，获取组织切片以评估脑损伤面积和死亡神经元的程度。将野生型小鼠的数据与蛋白酶激活受体-1基因敲除小鼠的结果进行比较。
在血液诱导的脑实质损伤中，水蛭素和GM6001均能显著减轻损伤，程度相当（>40%），这表明凝血酶和MMPs均参与神经毒性作用。在蛋白酶激活受体-1基因敲除小鼠中，血液诱导的脑损伤相对于野生型动物减少了22.6%；相比之下，使用GM6001时血液诱导的脑损伤减少了48.3%。
脑出血中血液的神经毒性涉及蛋白酶激活受体-1和MMP的激活，其中后者在导致细胞死亡方面似乎更为突出。
